Genetic Analysis and Midline Malignancies of Uncertain Origin

Abstract

One of the most difficult problems in oncology is the management of primary and metastatic neoplasms of uncertain histologic origin. In the case of metastatic neoplasms in adults, it has become clear that an exhaustive radiologic search for a primary site of origin merely empties the patient's pocketbook and squanders the meager remaining life span (/). The task of the clinician has been to make the best histologic diagnosis possible and to offer therapy appropriate to that diagnosis. The greatest challenge in the differential diagnosis of these patients has been the identification of malignant lymphomas, small cell or neuroendocrine carcinomas, and germ cell neoplasms. Correct diagnosis is important in order to identify patients with tumors that are especially responsive to specific regimens of systemic chemotherapy. In 1982, Hainsworth and colleagues (2) from Vanderbilt University (Nashville, TN) and the Indiana University Medical Center (Indianapolis) described a series of 32 patients with presumed advanced extragonadal germ cell tumors. Eighteen of the 31 evaluable patients (58%) experienced long-term diseasefree survival with cisplatin-based chemotherapy. A subsequent report from these investigators (3) has emphasized that most of these highly responsive tumors involve primarily midline body structures (midline tumors) and are often misdiagnosed as metastatic carcinoma or even as adenocarcinoma. More recently, Hainsworth and associates (4) have described an additional group of tumors involving midline structures that are not of germ cell origin. In that study, patients with those tumors usually did not have elevated serum levels of a-fetoprotein or Phuman chorionic gonadotropin, and electron microscopy demonstrated electron-dense (neurosecretory) granules within the tumor cells. In this issue of the Journal, Motzer and colleagues (5) from Memorial Sloan-Kettering Cancer Center (New York, NY) report their experience with genetic analysis as a diagnostic tool for patients with midline carcinomas of uncertain histology. Drawing on the observation that an isochromosome of the short arm of chromosome 12 [designated i(12p)] is a consistent cytogenetic abnormality in patients with germ cell tumors (6), these investigators studied nine patients with midline tumors of uncertain histology. One patient had a diagnosis of seminoma, but clinical features were atypical. Cytogenetic analysis subsequently established a diagnosis of non-Hodgkin's lymphoma based on the presence of a t(8;14)(q24;q32) abnormality. Of the other eight patients, with poorly differentiated carcinomas, four had abnormalities of chromosome 12 consistent with a germ cell tumor. Three of these four patients subsequently experienced a complete response to cisplatin-based chemotherapy. This study lends credence to the important role of i(12p), del(12q), and multiple copy numbers of 12p in patients with germ cell tumors. There is increasing evidence that most testicular tumors evolve through a seminomatous stage involving chromosomal deletions (7), and the data presented by Motzer and colleagues are consistent with that hypothesis. This theory may also explain why so many midline germ cell tumors cannot be diagnosed as such. They may well be diagnosed at a stage when they have developed chromosomal deletions or changes, but before all of the histologic characteristics of a germ cell tumor have developed. Certainly, these very early cytogenetic changes could occur without activating the genes needed to produce intracellular or increased extracellular concentrations of a-fetoprotein or (}-human chorionic gonadotropin. In short, it is likely that many of the patients with cisplatin-responsive midline neoplasms really do have poorly differentiated germ cell tumors. A critical factor in tissue analyses for standard histology, immunohistochemistry, and/or genetics is preparation of the tissue. Since major surgery in the chest or abdomen is usually required to obtain tissue, it is essential that the tissue be handled properly. This tissue should never be simply dropped in formalin and sent to the pathologist. The pathologist should be called to the operating room to prepare the tumor tissue. Deciding whether or not there is sufficient tissue for all necessary analyses requires the professional judgment of the pathologist, and this decision is best made while the surgical procedure is in progress and it is still possible to obtain additional tissue. The study by Motzer and associates (5) poses an interesting question about the relationship of specific genetic changes to the mechanism of action of antineoplastic agents. Specifically, could it be that the DNA conformational changes caused by the i(12p) anomaly render the cell peculiarly susceptible to the intrastrand cross-linking that occurs with cisplatin? Could other genetic changes lead to other patterns of selective toxicity? For example, could the cytogenetic changes often seen in malignant lymphomas, such as the t(8;14) anomaly seen by Motzer et al (5), lead to a higher degree of sensitivity to polyfunctional alkylating agents or the anthracycline antibiotics? These are, of course, unanswered questions, but they do suggest a new dimension to the problem of how to achieve selective toxicity. Could it be that the elusive search for exploitable qualitative differences between cancer cells and normal cells is to be found in these